Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance. Roitt, I., Brostoff, J. and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).
There is an enormous variety of cancers which are described in detail in the medical literature. Examples includes cancer of the blood, lung, colon, rectum, prostate, breast, brain, and intestine. The various forms of the cancers such as lymphomas are described in U.S. provisional application No. 60/380,842, filed May 17, 2002, the entireties of which are incorporated herein by reference (see, e.g., Section 2.2. Types of Cancers).
Lymphoma is a heterogenous group of neoplasms arising in the reticuloendothelial and lymphatic systems. The Merck Manual, 955 (17th ed. 1999). Non-Hodgkin's lymphoma (NHL) refers to malignant monoclonal proliferation of lymphoid cells in the immune system, including lymph nodes, bone marrow, spleen, liver and gastrointestinal (GI) tract. The Merck Manual, at 958.
Non-Hodgkin's lymphoma (NHL) is the fifth most common cancer for both men and women in the United States, with an estimated 63,190 new cases and 18,660 deaths in 2007. Jemal A, et al., CA Cancer J Clin 2007; 57(1):43-66. The probability of developing NHL increases with age and the incidence of NHL in the elderly has been steadily increasing in the past decade, causing concern with the aging trend of the US population. Id. Clarke C A, et al., Cancer 2002; 94(7):2015-2023.
The NHL classification embraces a heterogeneous group of diseases, originating from B and T lymphocytes, which can be clinically characterized as indolent, aggressive, or highly aggressive. Most patients with aggressive NHL have a diffuse large B-cell lymphoma (DLBCL). Cerny T, et al., Ann Oncol 2002; 13 Suppl 4:211-216.
Mantle-cell lymphoma (MCL) is a B-cell type lymphoma originating from the mantle zone of the lymph node. It accounts for 5-10% of all lymphomas and usually affects men over the age of 60. The MCL cells appear small with morphologic features similar to indolent lymphomas. For this reason, MCL was in the past grouped in the category of indolent lymphoma. However, the discovery of a characteristic chromosomal translocation involving the cyclin D1 gene, resulting in its unregulated overexpression, led to an improved ability to diagnose MCL and recognition that MCL had clinical behavior similar to aggressive lymphomas and one of the poorest survival rates among the lymphomas.
Peripheral T-cell lymphomas (PTCL) is a heterogenous group of neoplasms arising in the lymphatic systems. The Merck Manual, 955 (17th ed. 1999). Patients with T-cell lymphoma can present with disease in the head and neck region, but these tumors are less common than B-cell lymphomas. Siegel et. al., Review and current concepts. J Clin Oncol 2000 August; 18(15): 2908-25. In general, T-cell lymphomas involve the nodal regions, but skin involvement with cutaneous T-cell lymphomas can also occur. Extranodal NK/T-cell lymphomas specifically involve the nasal sinuses. These lymphomas are derived from mature T-cells and have been subdivided into a number of distinct pathologic entities.
Anticancer drugs cause rapid and persistent depletion of lymphocytes, possibly by direct apoptosis induction in mature T and B cells. K. Stahnke. et al., Blood 2001, 98:3066-3073. Absolute lymphocyte count (ALC) has been shown to be a prognostic factor in follicular non-Hodgkin's lymphoma and recent results have suggested that ALC at diagnosis is an important prognostic factor in diffuse large B-cell lymphoma. D. Kim et al., Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8082.
While patients who achieve a complete remission after initial therapy have a good chance for cure, less than 10% of those who do not respond or relapse achieve a cure or a response lasting longer than 3 years. Cerny T, et al., Ann Oncol 2002; 13 Suppl 4:211-216.
Further, rituximab is known to deplete normal host B cells. M. Aklilu et al., Annals of Oncology 15:1109-1114, 2004. The long-term immunologic effects of B cell depletion with rituximab and the characteristics of the reconstituting B cell pool in lymphoma patients are not well defined, despite the widespread usage of this therapy. Jennifer H. Anolik et al., Clinical Immunology, vol. 122, issue 2, February 2007, pages 139-145.
The approach for patients with relapsed or refractory disease relies heavily on experimental treatments followed by stem cell transplantation, which may not be appropriate for patients with a poor performance status or advanced age. Therefore, a tremendous demand exists for new methods that can be used to treat patients with NHL.